Basic research on articular cartilage biochemistry and metabolism has identified compounds (e.g., metalloproteinase inhibitors) that have shown great potential in animal models as disease-modifying drugs for osteoarthritis (DM0ADs). The osteoarthritis (0A) research community is in general agreement that narrowing of the joint space (JSN), measured in serial radiographs, is a surrogate for loss of articular cartilage that can, with standardized positioning of the subject be measured with sufficient accuracy to permit detection of a DMOAD effect. However, research on the effects of DM0ADs has been hampered by inconsistent and incomplete information on which to base decisions regarding the most appropriate target population(s) and primary outcome variables (i.e., measures reflecting progression of 0A). The study proposed herein will provide information which will be useful in the design Of future DMOAD trials; 260 subjects will be enrolled in a longitudinal study of 0A progression. All subjects will be greater then or equal to 45 years old and have idiopathic bilateral or unilateral knee 0A of mild-to- moderate radio graphic severity (i.e., essentially Kellgren and Lawrence Grade II-III: a definite osteophyte and medial tibiofemoral (TF) JSW is greater than 2 mm). Qualified subjects will undergo radio graphic examination and algofunctional assessment of 0A severity (WOMAC) at baseline and subsequently at 16 and 30 months. We will augment these data with parallel information from 36 subjects from the placebo group of a recently funded randomized controlled trial (RCT) of the effects of doxycycline on 0A progression--the protocol for which is identical to that for the present proposal with respect to the timing and technique of knee radiography and algofunctional assessment. All subjects from the RCT will be women, 45-64 years of age, with unilateral knee 0A and body mass index in.the upper tertile for women of the same age and race. Bony changes of TF and patellofemoral (PF) knee 0A (e.g., osteophytes, subchondral sclerosis) will be graded semiquantitatively while, for precision and generalizability to a future DMOAD trial, computerized measurements of minimum medial TF JSW will be made on digitized images of both knees, obtained with standardized positioning under fluoroscopy, with correction for image magnification.